RET Men2B -transgene Produces Sympathoadrenal Tumors But Does Not Prevent Intestinal Aganglionosis in gdnf −/− or gfrα-1 −/− Mice

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Abstract
Multiple endocrine neoplasia type 2B (MEN2B) syndrome is caused by a missense mutation in the RET gene, which replaces Met918 by Thr in the intracellular kinase domain of the protein. This single amino acid substitution transforms the receptor into a constitutively active monomeric kinase (RETMen2B) and produces an autosomal dominant syndrome characterized by medullary thyroid carcinoma, pheochromocytomas, musculoskeletal anomalies, and mucosal ganglioneuromas. The ligand, GDNF, stimulates RET activity through a co-receptor, GFRα-1. In vitro studies have shown that the kinase and mitogenic properties of RETMen2B are enhanced by GDNF/GFRα-1 stimulation. A relevant clinical question is whether ablation of either GDNF or GFRα-1 could alter penetrance or severity of the MEN2B syndrome. We report that ganglioneuromatous tumors caused by a RETMen2B transgene in mice are not affected grossly or microscopically by the absence of gdnf or gfrα-1. Loss-of-function mutations in ret, gdnf, or gfrα-1 cause pan-intestinal aganglionosis in mice. We find that expression of the RETMen2B transgene in enteric neural progenitors, after they colonize the gut, does not prevent intestinal aganglionosis associated with gdnf or gfrα-1 deficiency.

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